The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has a variety of functions in the central nervous system. It has been implicated in many cognitive and behavioral functions, including aggression, sexual behavior, learning and sleep. Disruptions of serotonergic systems may be a critical factor in a number of clinical disorders or conditions including schizophrenia, depression, obsessive compulsive disorder, anxiety, migraine headaches, and pain.
The multitude of effects produced by serotonin are mediated by various serotonin receptors which exist in the central and peripheral nervous system. The transduction of serotonergic signals across the neuronal membrane is mediated by a diversity of receptor subtypes which, in mammals, appear to fall into four pharmacologically distinct classes designated 5-HT1-5-HT4. The 5HT1 subcategory has been further subdivided into five different subtypes referred to as 5HT1A-E. The primary structures for a number of these receptors have been elucidated by molecular cloning, including the 5-HT1, 5-HT2 and 5HT3 subclasses. In addition, the sequences of three different Drosophila serotonin receptors, 5-HTdro1 and 5-HTdro2A,B, have been reported.
Selective therapeutic agents, including agonist and antagonist drugs, have been developed based on serotonin receptor technologies. 5-HT2 antagonists, for example, are useful in the treatment of schizophrenia, parkinsonism, and anxiety disorders. Several azapirones, such as buspirone, gepirone, and ipsapirone, have high affinities for 5HT1A receptors in the brain, and are useful in the treatment of anxiety. Highly selective 5-HT uptake inhibitors, which have minimal effects on norepinephrine or dopamine uptake or on other neurotransmitter receptors, have been used to successfully treat depression.
Characterization of all specific 5-HT receptors would clarify the role of serotonin in the central nervous system. Analysis of the receptor subtypes and their functional role in the central nervous system would help elucidate the pathophysiological basis of many human diseases. Accordingly, there is a need for identification and characterization of all specific 5-HT receptors, and the development of selective therapeutic agents based on these receptor technologies.